KR20200011490A - Enhancement of brain function, food and medicine using lipopolysaccharide - Google Patents
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Abstract
판토에아균 LPS를 알츠하이머병 모델 마우스에 대하여 경구 투여하고, 그 영향을 조사한 결과, 판토에아균 LPS의 경구 투여에 의해, 뇌내의 Aβ 펩티드 축적량이 유의하게 감소하는 것, 학습 기능이 개선되는 것을 발견함으로써, 용이하게 입수 가능한, Aβ 뇌내 침착의 억제 효과 또는 학습기능의 개선 효과를 갖는 뇌기능 개선제 또는 식품 조성물을 제공한다.As a result of oral administration of Pantoea LPS to mice with Alzheimer's disease, the results of the investigation revealed that oral administration of Pantoea LPS significantly reduced Aβ peptide accumulation in the brain and improved learning function. Thereby, the brain function improving agent or the food composition which has the inhibitory effect of A (beta) intracranial deposition or the improvement effect of learning function which is easily available is provided.
Description
본 발명은 리포 다당을 함유하는 뇌기능 개선제, 식품 및 의약품에 관한 것이다.The present invention relates to brain function improving agents, foods and pharmaceuticals containing lipopolysaccharide.
최근, 일본에서는 총 인구가 감소하는 한편, 65세 이상의 고령자 인구는 해마다 증가 경향에 있다. 후생 노동부에 의하면, 고령자 인구(2015년)는 3300만명을 넘어, 고령화율은 26.7%에 달하고 있다고 하고 있다. 고령자 질환의 하나인 인지증에 있어서는, 일본 내의 환자수는 현재 460만명을 넘었고, 2025년에는 700만명, 고령자의 5명에 1명이 될 것으로 예상되고 있다. 인지증 환자의 약 60%는 알츠하이머병, 약 20%가 혈관성 인지증이며, 나머지는 레비 소체형 인지증 등의 여러 인지증 질환이 포함되어 있다. 알츠하이머병의 임상 증상은 기억 장애나 언어 장애 등의 인지기능 장애, 정신증상, 행동장애 등이다. 알츠하이머병의 병리학적 특징으로서 아밀로이드반이라도고 불리는 노인성반과 신경원섬유 변화 등의 이상 구조물이 대뇌 피질·해마의 광범위에 침착하는 것이 있다. 아밀로이드반의 주 구성성분은 아밀로이드 β단백질(이하, 단지 「Aβ」라고도 함)이며, 특히, 42 잔기로 이루어지는 Aβ펩티드(이하, 단지 「Aβ1-42」라고도 함)는 응집성이 높아, 아밀로이드 침착에 중핵적인 역활을 수행하는 것이 알려져 있다. 후자는 과잉으로 인산화된 타우 단백질이다. 현재, 알츠하이머병의 병리 캐스케이드로서 아밀로이드 가설이 일반적으로 지지받고 있다. Aβ의 과잉 축적에 의한 아밀로이드반의 형성, 타우 단백질의 축적(신경원섬유 변화), 이어서 신경변성·신경세포사에 이른다고 하는 시계열이다(비특허문헌 1). 정상인의 뇌 내에서도 가령과 함께 Aβ는 출현하지만, Aβ 생산에 관계되는 효소의 유전자 변이 또는 Aβ 분해계의 활성 저하에 의해, Aβ 축적이 촉진된다고 여겨지고 있다. 알츠하이머병의 치료약으로서는 신경전달 물질이나 그 수용체를 표적으로 한 치료약(아세틸콜린에스테라제 저해약이나 N-메틸-D-아스파르트산 수용체 길항약)이 개발되어 왔지만, Aβ의 축적이나 타우 단백질의 응집 등의 병리 변화를 치료하는 치료약이 아니기 때문에, 알츠하이머병의 진행을 저지할 수 있는 근본적인 치료약이 아니다.In recent years, the total population has decreased in Japan, while the elderly population 65 years or older tend to increase year by year. According to the Ministry of Health, Labor and Welfare, the elderly population (2015) is over 33 million, and the aging rate reaches 26.7%. In dementia, one of the elderly diseases, the number of patients in Japan is currently over 4.6 million, and it is expected that by 2025, 7 million people will be 1 in 5 people. About 60% of dementia patients are Alzheimer's disease, about 20% are vascular dementia, and the remainder includes several dementia diseases such as Lewy body dementia. Clinical symptoms of Alzheimer's disease include cognitive impairments such as memory and speech impairments, mental symptoms, and behavioral disorders. As a pathological feature of Alzheimer's disease, abnormal structures such as amyloid plaques and neurofibrillary tangles, called amyloid plaques, are deposited in a wide range of cerebral cortex and hippocampus. The major component of amyloid plaques is amyloid β-protein (hereinafter also referred to simply as “Aβ”). In particular, Aβ peptides (hereinafter referred to simply as “Aβ1-42”) consisting of 42 residues are highly cohesive and are the core for amyloid deposition. It is known to play a role. The latter is excessively phosphorylated tau protein. Currently, the amyloid hypothesis is generally supported as a pathological cascade of Alzheimer's disease. Formation of amyloid plaques due to excessive accumulation of Αβ, accumulation of tau protein (neurofibrillary fibrous change), followed by neurodegeneration and neuronal cell death (Non-Patent Document 1). Aβ appears in the brain of a normal person, for example, but it is believed that Aβ accumulation is promoted by gene mutation of an enzyme involved in Aβ production or by deactivation of the Aβ degradation system. As drugs for treating Alzheimer's disease, drugs that target neurotransmitters and their receptors (acetylcholinesterase inhibitors and N-methyl-D-aspartic acid receptor antagonists) have been developed, but accumulation of Aβ and aggregation of tau protein Because it is not a cure for treating pathological changes in the back, it is not a fundamental cure that can arrest the progression of Alzheimer's disease.
한편, 뇌조직의 대식세포인 마이크로글리아는 손상을 받은 조직의 수복, 뇌 내에서의 노폐물의 탐식 제거 등, 뇌 내의 항상성(homeostasis) 유지에 중요한 역할을 담당하는 것이 명확하다고 되어 있다. 마이크로글리아는 Aβ 수용체를 발하고 있어, 탐식 반응에 의해 Aβ의 섭취·분해를 행하는 점에서, 마이크로글리아의 Aβ 탐식 능력 활성화를 활성화시킴으로써 Aβ의 과잉 축적을 기인으로 하는 알츠하이머병의 예방을 기대할 수 있다. 최근, 마이크로글리아의 Aβ 탐식 능력을 활성화할 수 있는 작용을 갖는 화합물의 탐색이 진척되고 있으며, 올레산 아미드(비특허문헌 2)나 펩티드(특허문헌 1) 등의 식품 성분이 in vitro 실험계에서 효과가 보고되고 있다.On the other hand, microglia, which are macrophages of brain tissue, have been shown to play an important role in maintaining homeostasis in the brain, such as repairing damaged tissues and eliminating waste products from the brain. Since microglia emits Aβ receptor and ingests and degrades Aβ by a phagocytosis reaction, it is expected to prevent Alzheimer's disease due to excessive accumulation of Aβ by activating Ag phagocytic activation of microglia. Can be. Recently, the search for a compound having a function of activating the Aβ phagocytosis ability of microglia has been progressed, and food ingredients such as oleic acid amide (non-patent document 2) and peptide (patent document 1) are effective in in vitro experimental systems. Is being reported.
그런데, 리포 다당은 그람음성균의 세포벽의 외막 성분의 하나이다. 콜레라균 유래 독성 물질에 대하여 엔도톡신이라고 하는 명칭이 1892년에 주어졌고, 엔도톡신의 본체가 리포 다당인 것이 1954년에 보고되었다(비특허문헌 3). 그러나, 최근, 알츠하이머병 모델 마우스에 대한 리포 다당의 두개내 주사는 마이크로글리아의 활성화를 유도하여, Aβ의 뇌 내 침착을 억제하는 것이 보고되었다(비특허문헌 4). 마찬가지로, 리포 다당의 구성성분인 리피드 A의 유도체이며, 아쥬반트(면역부활제)로서 인가되어 있는 MPL(Monophosphoryl lipid A)의 복강내 주사는 Aβ 뇌내 침착 억제 작용 및 학습기능 개선 작용을 보이는 것이 보고되었다(비특허문헌 5). 한편, 리포 다당의 경구 또는 경피에 의한 섭취에서는, 명확한 독성이 확인되지 않고, 고지혈증이나 알레르기 등의 질환에 대한 개선 효과를 보인다는 보고가 있다(비특허문헌 6). 소마 등은 이 리포 다당의 하나가 소맥공생세균 판토에아·아글로메란스(Pantoea agglomerans)에 유래하는 리포 다당(이하, 「판토에아균 LPS」라고도 함)인 것을 발견하고, 화장품, 식품, 기능성 식품 등에 첨가해도 안전한 리포 다당을 얻기 위한 발효 및 배양 방법을 보고했다(특허문헌 2). 후카사카 등은 설하 투여된 판토에아균 LPS는 아쥬반트로서 작용하여, 점막의 면역 활성을 높이는 것을 동물 실험에서 보고했다(비특허문헌 7). 또한, 코바야시 등은 마우스 뇌 유래 마이크로글리아의 초대 세포를 사용한 검토에 의해, 판토에아균 LPS가 Aβ1-42에 대한 탐식 능력을 향상시키는 것을 보고했다(비특허문헌 8). 그런데 경구 투여한 리포 다당은 소화관으로부터는 거의 흡수되지 않는다. 이것이, 예를 들면, 전분이면, 인간은 전분(글루코오스의 α1-4 결합하고 있는 고분자 다당)을 소화하는 효소(아밀라아제, 말타아제)를 가지고 있기(위키피디아, 전분) 때문에 소화되지만, LPS의 다당은 3-5종류의 6탄당이나 5탄당으로 이루어지는 구조로(위키피디아, 리포 다당), 인간은 LPS의 다당 구조에 대하여 분해할 수 있는 소화 효소를 가지고 있지 않기 때문에, 소화되지 않는다. 또 뇌내 이행에 관해서는 뇌혈액관문이 있는 것 등에 의해, 가령 경구 투여에 의해 리포 다당이 혈액 중에 흡수되었다고 해도 뇌내 이행은 또한 효율이 저하되게 되므로, 경구 투여한 리포 다당은 뇌내까지 도달하지는 않는다고 생각된다. 말할 것도 없이 리포 다당의 경구 투여에 의한 Aβ 뇌내 침착 억제 효과 또는 학습기능 개선 효과는 지금까지 보고되어 있지 않으며, 어느 문헌에도 기재되어 있지 않다.By the way, lipopolysaccharide is one of the outer membrane components of the cell wall of Gram-negative bacteria. The name endotoxin was given in 1892 for cholera-derived toxic substances, and it was reported in 1954 that the main body of the endotoxin was lipopolysaccharide (Non-Patent Document 3). Recently, however, intracranial injection of lipopolysaccharide into Alzheimer's disease model mice has been reported to induce microglia activation and inhibit the deposition of Aβ in the brain (Non-Patent Document 4). Similarly, intraperitoneal injection of lipid A, a constituent of lipopolysaccharide and applied as an adjuvant (immunostimulator), has been reported to show inhibition of Aβ brain deposition and improvement of learning function. (Nonpatent literature 5). On the other hand, ingestion by lipopolysaccharide orally or transdermally, no clear toxicity is confirmed, and there is a report showing improvement effect on diseases such as hyperlipidemia and allergy (Non Patent Literature 6). Soma et al. Discovered that one of these lipopolysaccharides is lipopolysaccharide (hereinafter also referred to as `` pantoea bacterium LPS '') derived from wheat symbiosis bacteria Pantoea agglomerans. The fermentation and culture method for obtaining the lipopolysaccharide which is safe even if added to food etc. was reported (patent document 2). Fukasaka et al. Reported in animal experiments that sublingually administered pantoea bacteria LPS acted as an adjuvant to increase mucosal immune activity (Non-Patent Document 7). In addition, Kobayashi et al. Reported that pantoea bacteria LPS improves the phagocytosis of Aβ1-42 by examination using primary cells of mouse brain-derived microglia (Non-Patent Document 8). However, orally administered lipopolysaccharide is hardly absorbed from the digestive tract. If this is, for example, starch, humans are digested because they have enzymes (amylase, maltase) that digest starch (the α1-4 -binding macromolecule of glucose) (Wikipedia, starch), but LPS polysaccharide is 3 The structure consists of five types of hexasaccharides and pentoses (Wikipedia, Lipopolysaccharides), and since humans do not have digestive enzymes capable of degrading the polysaccharide structure of LPS, they are not digested. In addition, regarding the transition to the brain, even if lipopolysaccharide is absorbed into the blood by oral administration, for example, the efficiency in the brain also decreases, so the lipopolysaccharide administered orally does not reach the brain. do. Needless to say, the effect of inhibiting A [beta] deposition in the brain or the improvement of learning function by oral administration of lipopolysaccharide has not been reported so far and is not described in any literature.
뇌내 Aβ 침착의 억제 효과 또는 학습기능의 개선 효과는 인지증, 특히 알츠하이머병의 예방에 유용하다고 여겨지고 있다. 본 발명은 이상과 같은 배경을 감안하여 이루어진 것으로서, 상기의 발효배양법(특허문헌 2)에 의해 비교적 용이하게 입수 가능한 리포 다당에 의한 Aβ 뇌내 침착의 억제 효과 또는 학습기능의 개선 효과를 갖는 뇌기능 개선제, 식품 및 의약품을 제공하는 것을 과제로 한다.The inhibitory effect of Aβ deposition in the brain or the improvement of learning function is considered to be useful for the prevention of dementia, especially Alzheimer's disease. The present invention has been made in view of the above-described background, and has a brain function improving agent having an inhibitory effect of Aβ intracranial deposition by lipopolysaccharide, which can be obtained relatively easily by the fermentation culture method (Patent Document 2), or an improvement effect of learning function. To provide food, medicine and medicine.
본 발명자들은 상기 과제를 해결하기 위해 예의 검토했다. 판토에아균 LPS를 알츠하이머병 모델 마우스에 대하여 경구 투여하고, 그 영향을 조사했다. 그 결과, 판토에아균 LPS의 경구 투여에 의해, 뇌내의 Aβ 펩티드 축적량이 유의하게 감소하는 것, 학습기능이 개선되는 것을 발견하고, 본 발명을 완성했다. 본 발명의 뇌기능 개선제는 판토에아균 LPS를 유효 성분으로서 함유하는 것을 특징으로 하는, 알츠하이머병에 대한 것이다.The present inventors earnestly examined in order to solve the said subject. Pantoea LPS was orally administered to Alzheimer's disease model mice and its effects were investigated. As a result, it was found that the oral administration of Pantoea bacillus LPS significantly reduced the amount of Aβ peptides accumulated in the brain and improved learning function, thus completing the present invention. The brain function improving agent of the present invention is directed to Alzheimer's disease, characterized by containing Pantoea LPS as an active ingredient.
즉 본 발명은 하기의 구성을 갖는 것이다.That is, this invention has the following structures.
(1) 판토에아균 LPS로 이루어지는 리포 다당을 유효 성분으로 하는, 뇌기능 개선제, 식품 또는 의약품.(1) Brain function improving agent, food or pharmaceutical product which uses lipopolysaccharide which consists of Pantoea bacteria LPS as an active ingredient.
(2) 개선되는 뇌기능이 가령 또는 가령에 따른 뇌질환에 기인하여 저하된 인지기능인 것을 특징으로 하는 청구항 1의 뇌기능 개선제, 식품 또는 의약품.(2) The brain function improving agent, food or medicine according to
(3) 판토에아균 LPS를 유효량 함유하는, 청구항 1에 기재된 뇌기능 개선제, 식품 또는 의약품.(3) The brain function improving agent, food or medicine according to
(4) 알츠하이머병을 예방하기 위한, 청구항 1에 기재된 뇌기능 개선제, 식품 또는 의약품.(4) The brain function improving agent, food or medicine according to claim 1 for preventing Alzheimer's disease.
(5) 판토에아균 LPS를 1일 투여 단위당 0.1∼1mg/kg 체중의 비율로 함유하는 청구항 1에 기재된 뇌기능 개선제, 식품 또는 의약품.(5) The brain function improving agent, food or medicine according to
본 발명에 의하면, 판토에아균 LPS에 의해, 알츠하이머병의 예방 효과, 특히, Aβ 뇌내 침착의 억제 효과 및 학습기능 개선 효과를 갖는 약제, 식품 등의 조성물을 제공할 수 있다. 판토에아균 LPS는 식품용, 화장품용, 사료용 등의 형태에 따른 경구 또는 경피 투여에 있어서의 안전성이 확인되었으므로, 부작용의 위험이 작은 예방 효과를 기대할 수 있다.ADVANTAGE OF THE INVENTION According to this invention, the composition of drugs, foods, etc. which have the preventive effect of Alzheimer's disease, especially the inhibitory effect of A (beta) brain deposition and the improvement of learning function can be provided by pantoea bacterium LPS. Pantobacteria LPS has been confirmed safety in oral or transdermal administration according to the form of food, cosmetics, feed, etc., can be expected to have a small preventive effect of the risk of side effects.
도 1은 수중 미로 시험에 있어서의 트레이닝 시험의 결과를 나타내는 것이다. 연속된 5일간의 트레이닝에 의해, 플랫폼 도달에 요하는 시간은 모든 군에서 단축된 것을 나타내는 그래프이다. 또한, 군 사이에서의 차는 확인되지 않았다.
도 2는 수중 미로 시험에 있어서의 프로브 시험에서의 대표적인 수영 궤적을 나타낸 것이다. 점선의 원은 플랫폼이 설치되어 있었던 위치를 나타내고 있다.
도 3은 수중 미로 시험의 프로브 시험에 있어서, 플랫폼이 설치되어 있었던 4분원 영역에 마우스가 체류하고 있었던 시간의 결과를 나타낸 것이다. 고지방 사료를 섭취한 PC군에서는 체류 시간의 감소가 확인되고 있는 것에 반해, 판토에아균 LPS 섭취는 체류 시간을 연장시키는 것을 나타내는 결과이다.
도 4는 18주간 사육 후의 마우스로부터 적출한 뇌에서의 Aβ(Aβ1-40 및 Aβ1-42)의 축적량을 나타낸다. 고지방 사료를 섭취한 PC군에서는, NC군과 비교하여, Aβ1-40량의 유의한 상승이 확인되고 있어, 판토에아균 LPS 섭취는 PC군과 비교하여, Aβ1-40 및 Aβ1-42량을 유의하게 저하시키는 것을 나타내는 결과이다.1 shows the results of a training test in an underwater maze test. With five consecutive days of training, the time required to reach the platform is a graph showing shortening in all groups. In addition, the difference between groups was not confirmed.
2 shows a representative swimming trajectory in the probe test in the underwater maze test. The dotted circle indicates the position where the platform was installed.
Fig. 3 shows the results of the time when the mouse stayed in the quadrant region where the platform was installed in the probe test of the underwater maze test. In the PC group fed high fat feed, the reduction of the residence time was confirmed, whereas ingestion of Pantoea bacteria LPS is a result of prolonging the residence time.
4 shows the accumulation of Aβ (Aβ1-40 and Aβ1-42) in the brains extracted from mice after 18 weeks of breeding. In the PC group fed high fat diet, significant increase of Aβ 1-40 was observed compared to NC group, and Pantoea LPS intake was significantly higher in Aβ 1-40 and Aβ 1-42 compared with PC group. This is a result showing that the lowering.
(발명을 실시하기 위한 형태)(Form to carry out invention)
본 발명의 뇌기능 개선제 및 식품 조성물은 판토에아균 LPS를 함유한다.The brain function improving agent and the food composition of the present invention contain pantoea LPS.
여기에서, 「판토에아균 LPS」는 특별히 기재한 경우를 제외하고, 특허문헌 2에 기재된 수순에 따라, 소맥에 공생하는 그람음성균의 판토에아·아글로메란스(Pantoea agglomerans)를 소맥분에서 배양하고, 균체로부터 리포 다당을 열수 추출하고, 고형분을 제거한 리포 다당을 가리킨다.Herein, except for the case where the pantoea bacterium LPS is specifically described, Pantoea agglomerans of Gram-negative bacteria that coexist in wheat flour are cultured in wheat flour according to the procedure described in
본 발명의 뇌기능 개선제 및 식품은 가령 또는 가령에 수반되는 뇌질환에 기인하는 뇌기능 장애, 특히 인지 기능 장애를 개선할 수 있다. 인지 기능 장애를 수반하는 뇌질환으로서는, 예를 들면, 알츠하이머병 등을 명시할 수 있다.Brain function improving agents and foods of the present invention can ameliorate brain dysfunction, in particular cognitive dysfunction due to, for example, or accompanying brain diseases. As a brain disease accompanying a cognitive dysfunction, Alzheimer's disease etc. can be specified, for example.
본 발명의 판토에아균 LPS는 인간, 인간 이외의 포유류(돼지, 소, 양, 말, 개, 고양이 등의 가축), 조류(닭, 칠면조, 집오리 등의 가금) 등에 적용할 수 있다.The pantoea bacterium LPS of the present invention can be applied to humans and non-human mammals (animals such as pigs, cattle, sheep, horses, dogs, cats), birds (poultry such as chickens, turkeys, ducks) and the like.
본 발명의 의약 조성물의 투여 경로, 제형은 목적, 증상, 대상자의 연령, 체중 등에 따라 적당히 설계할 수 있다. 투여 경로의 예로서는 경구 투여, 경피 투여, 구강 투여, 피하 주사, 피내 주사, 복강내 주사, 근육내 투여 등이 있다. 바람직하게는, 경구 투여, 경피 투여, 구강 투여이다. 제형의 형으로서는 산제, 과립제, 액제, 캡슐, 세립제, 환제, 시럽제, 유제 등을 들 수 있다. 이 의약 조성물은 경구 투여가 가능하며, 또한 유효하다. 이들 제제는 판토에아균 LPS에 더하여, 의약품으로서 허용 가능한 여러 첨가물, 예를 들면, 안정화제, 충전제, 유화제, 증량제, 부형제, 결합제, 보습제, 붕괴제, 계면활성제, 현탁제, 코팅제, 착색제, 향료, 풍미제, 감미제, 보존제, 산화방지제를 함유시킬 수 있다.The route of administration, the dosage form, and the like of the pharmaceutical composition of the present invention can be appropriately designed according to the purpose, symptoms, age, weight, etc. of the subject. Examples of routes of administration include oral administration, transdermal administration, oral administration, subcutaneous injection, intradermal injection, intraperitoneal injection, intramuscular administration and the like. Preferably, oral administration, transdermal administration, oral administration. Examples of the dosage form include powders, granules, solutions, capsules, fine granules, pills, syrups, emulsions, and the like. This pharmaceutical composition can be administered orally and is also effective. These formulations, in addition to Pantoea LPS, include a variety of acceptable additives as pharmaceuticals, such as stabilizers, fillers, emulsifiers, extenders, excipients, binders, humectants, disintegrants, surfactants, suspensions, coatings, colorings, flavorings , Flavoring agents, sweetening agents, preservatives, and antioxidants.
본 발명의 식품 조성물은 판토에아균 LPS를 그대로 사용하고, 또는 다른 식품 또는 식품 성분과 혼합하는 등, 식품 조성물에 있어서의 상법에 따라 사용할 수 있다. 또한, 그 형태에 대해서도, 특별히 제한되지 않고, 통상 사용되는 식품의 상태, 예를 들면, 고체상(분말, 과립상 등), 페이스트상, 액상 또는 현탁상의 어떤 것이어도 된다. 본 발명의 식품 조성물은 영양기능 식품, 특정 보건용 식품, 기능성 표시 식품, 건강 식품, 영양 보조 식품, 드링크제, 청량 음료, 알코올 음료, 서플리먼트, 사료, 사료 첨가물 등으로 할 수 있다.The food composition of this invention can be used according to the commercial method in a food composition, using Pantoea bacillus LPS as it is, or mixing with another foodstuff or food component. In addition, the form is not particularly limited either, and may be any of a state of a foodstuff that is usually used, for example, solid (powder, granular, etc.), paste, liquid or suspension. The food composition of the present invention may be a nutritional functional food, a specific health food, a functional labeling food, a health food, a nutritional supplement, a drink, a soft drink, an alcoholic beverage, a supplement, a feed, a feed additive.
본 발명의 뇌기능 개선제 또는 식품 조성물은, 경구 섭취의 경우, 판토에아균 LPS를, 성인 1일당 0.1∼1mg/kg 체중의 범위에서 함유하도록 배합되는 것이 바람직하고, 1∼수 회로 나누어서 투여할 수 있다. 바람직하게는 0.3∼1mg/kg 체중, 보다 바람직하게는 0.5∼1mg/kg 체중이다. 이러한 용량은 대상자의 연령, 체중, 건강 상태, 투여 방법 및 다른 제제(또는 식품 성분)와의 조합 등의 여러 인자에 따라 적당히 조정할 수 있다. 장기간에 걸쳐 예방의 목적으로 섭취하는 경우에는, 상기 범위보다 소량이어도 된다.In the case of oral ingestion, the brain function improving agent or the food composition of the present invention is preferably formulated so as to contain Pantoea bacillus LPS in the range of 0.1 to 1 mg / kg body weight per adult, and can be administered by dividing once to several times. have. Preferably it is 0.3-1 mg / kg body weight, More preferably, it is 0.5-1 mg / kg body weight. Such doses may be appropriately adjusted depending on various factors such as the subject's age, weight, health condition, method of administration and combination with other agents (or food ingredients). When ingested for the purpose of prophylaxis over a long period, the amount may be smaller than the above range.
실시예Example
이하, 실시예에 따라 본 발명을 보다 상세하게 설명하지만, 본 발명은 이하의 실시예에 제한되는 것은 아니다.Hereinafter, although an Example demonstrates this invention in detail, this invention is not restrict | limited to the following example.
[실시예 1] 알츠하이머병 모델 마우스에 대한 판토에아균 LPS의 경구 투여 시험 방법Example 1 Oral Administration Test Method of Pantoea LPS in Alzheimer's Disease Model Mice
판토에아균 LPS는 소마 등이 개발한 리포 다당의 발효 배양법(특허문헌 2)에 따라, 조제·정제된 것(Lipopolysaccharide, Pantoea agglomerans <LPS>, 자연면역 응용 기술 연구소사)을 사용했다. 실험에는, 알츠하이머병 모델 마우스로서 12-14주령의 수컷 SAMP8 마우스(Senescence accelerated mouse-prone 8/Ta Slc, 닛폰 SLC사)를 사용하여, 1주간 예비 사육 후, 체중에 따라 4군으로 나누었다. 35% 지방을 포함하는 사료(리서치 다이어트)를 주고, 0.3 또는 1mg/kg 체중/day의 판토에아균 LPS를 포함하는 물을 자유 음수에 의한 경구 투여로 주었다. 또한, 컨트롤군에는, 35% 지방을 포함하는 사료 또는 4% 지방을 포함하는 사료(리서치 다이어트)를 주고, 동일한 방법으로 물을 주었다. 마우스의 사육은 온도 습도 관리된 동물 시설에서, 자유 섭식, 자유 음수, 12시간 광 조사/12시간 암흑하의 환경 조건에서 행했다. 17주간 사육 후, 이하에 나타내는 수중 미로 시험을 1주간 행하고, 학습기능을 평가했다. 수중 미로 시험 종료의 다음날, 심장으로부터 채혈을 했다. 뇌, 간장, 정소 상체 주위 백색 지방세포를 적출했다. 본 동물 실험은 카가와 대학 동물 실험 위원회에 의해 승인되었다.The pantoea bacteria LPS was prepared and purified according to the fermentation culture method of lipopolysaccharide (Patent Document 2) developed by Soma et al. (Lipopolysaccharide, Pantoea agglomerans <LPS>, Natural Immunology Research Institute). In the experiment, 12-14-week-old male SAMP8 mice (Senescence accelerated mouse-prone 8 / Ta Slc, Nippon SLC Co., Ltd.) were used as Alzheimer's disease model mice, and were divided into four groups according to body weight after one week of preliminary breeding. A feed containing 35% fat (research diet) was given and water containing 0.3 or 1 mg / kg body weight / day of Pantoea LPS was given by oral administration by free negative water. In addition, the control group was given a feed containing 35% fat or a feed containing 4% fat (research diet) and watered in the same manner. The breeding of mice was carried out in an animal facility in a temperature-humidity controlled environment under free feeding, free negative water, 12 hours light irradiation / 12 hours dark environment. After breeding for 17 weeks, the underwater maze test shown below was performed for 1 week, and the learning function was evaluated. The day after the end of the underwater maze test, blood was drawn from the heart. White fat cells around the brain, liver, and testis were extracted. This animal experiment was approved by the Kagawa University Animal Experiment Committee.
이 실시예에서는, 알츠하이머병 모델 마우스로서 수컷 SAMP8 마우스를 사용했다. 본 마우스는 가령에 따라, 뇌내 Aβ 침착량의 증가나 학습기능의 저하 등, 알츠하이머병 유사 증상을 보이므로, 노화 촉진 모델 마우스로서 사용되었다(비특허문헌 9). 또한 고지방식의 섭취는 2형 당뇨병 유사의 증상, 예를 들면, 공복일 때 혈당값의 증가, HbA1c값의 증가 등을 유도함으로써 알츠하이머병의 진전을 가속화 하는 것이 보고되었다(비특허문헌 10).In this example, male SAMP8 mice were used as Alzheimer's disease model mice. This mouse was used as an aging promoting model mouse because it exhibits Alzheimer's disease-like symptoms such as an increase in the amount of Aβ deposition in the brain and a decrease in learning function, for example (Non-Patent Document 9). In addition, high-fat ingestion has been reported to accelerate the development of Alzheimer's disease by inducing symptoms of
본 실시예에서는, 마우스를 이하의 4군으로 나누었다.In this example, mice were divided into the following four groups.
(1) NC군: 4% 지방을 포함하는 사료(저지방 사료) 및 물을 자유 섭취하게 했다.(1) NC group: Free feed containing 4% fat (low fat diet) and water.
(2) PC군: 35% 지방을 포함하는 사료(고지방 사료) 및 물을 자유 섭취하게 했다.(2) PC group: Free intake of water containing 35% fat (high fat feed) and water.
(3) 판토에아균 LPS 0.3mg/kg 체중/day군: 고지방 사료 및 판토에아균 LPS(0.3mg/kg 체중/day)를 포함하는 물을 자유 섭취하게 했다.(3) Pantoea LPS 0.3 mg / kg body weight / day group: A high-fat diet and water containing Pantoea LPS (0.3 mg / kg body weight / day) were allowed to be ingested freely.
(4) 판토에아균 LPS 1mg/kg 체중/day군: 고지방 사료 및 판토에아균 LPS(1mg/kg 체중/day)를 포함하는 물을 자유 섭취하게 했다.(4)
[수중 미로 시험][Underwater maze test]
(1) 장치(1) device
원통형 풀(직경 100cm, 깊이 40cm)에 물(23±1℃)을 넣고, 투명한 플랫폼(직경 10cm)이 수면 아래 1cm에 가라앉도록 설치했다. 시판의 흑색 잉크를 풀의 물에 넣어, 수영 중의 마우스가 플랫폼을 시인할 수 없도록 했다. 풀 수면의 바로 위에 시판의 디지털 카메라를 설치하고, 마우스의 수영을 동화상으로 기록했다. 수영 궤적의 해석은 화상 해석 소프트웨어 Aminal Tracker를 사용하여, 「Neuroinformatics, 14, 479-481, 2016」 기재의 방법에 따라 행했다.Water (23 ± 1 ° C.) was placed in a cylindrical pool (100 cm in diameter and 40 cm in depth) and the transparent platform (10 cm in diameter) was settled down to 1 cm below the water surface. Commercial black ink was added to the water of the pool so that the swimming mouse could not see the platform. A commercial digital camera was installed just above the pool surface, and the swimming of the mouse was recorded as a moving picture. The swimming trajectory was analyzed according to the method described in "Neuroinformatics, 14, 479-481, 2016" using image analysis software Aminal Tracker.
(2) 수순(2) procedure
시험 전날에, 마우스가 풀에 친숙하게 하기 위해, 각각 1회 헤엄치게 했다. 수순은 수면 위 1cm에 고정한 플랫폼에 마우스를 20초간 정치한 뒤, 30초간 자유롭게 헤엄치게 했다. 그 후, 실험자의 손으로 마우스를 플랫폼 위로 유도하고, 20초간 정치했다. 또한 풀에 넣을 때는 마우스를 풀의 벽 방향으로 입수시키고, 실험자는 신속하게 마우스로부터 보이지 않는 위치로 이동했다. 1∼5일째는 마우스에 플랫폼의 위치를 기억시키는 트레이닝을 실시했다. 트레이닝은 1일에 4회 연속하여 행했다. 트레이닝의 수순은 마우스를 임의의 위치에서 풀에 넣고, 60초간 헤엄치게 하고, 수면 아래 1cm에 설치한 플랫폼을 탐색시켰다. 플랫폼 도달에 요하는 시간을 기록하고, 60초에 도달할 수 없는 경우에는 60초로 기록했다. 또한 시간 내에 플랫폼에 도달하지 못한 마우스는 실험자의 손으로 플랫폼으로 유도했다. 플랫폼에 도달 후, 20초간 정치하고, 마우스를 풀로부터 꺼냈다. 6일째에 프로브 시험을 행했다. 프로브 시험은 풀로부터 플랫폼을 제거하고, 마우스를 60초간 헤엄치게 하고, 풀의 각 4분원 영역 내에서의 체류 시간을 측정했다. 또한, 프로브 시험은 각 마우스에 대해 1회 행했다.The day before the test, the mice were swimming once each to familiarize themselves with the pool. The procedure allowed the mouse to rest on the platform fixed at 1cm above the surface for 20 seconds, and then freely swim for 30 seconds. The mouse was then guided onto the platform with the hands of the experimenter and left to stand for 20 seconds. In addition, when entering the pool, the mouse was obtained in the direction of the wall of the pool, and the experimenter quickly moved from the mouse to an invisible position. On days 1-5, the mouse was trained to memorize the position of the platform. Training was performed four times a day in succession. The procedure for training was to move the mouse into the pool at any position, swim for 60 seconds, and search for a platform installed 1 cm below the surface of the water. The time required to reach the platform was recorded and 60 seconds if it could not be reached. In addition, mice that did not reach the platform in time were guided to the platform by the experimenter's hand. After reaching the platform, it was left standing for 20 seconds and the mouse was taken out of the pool. The probe test was done on the 6th day. The probe test removed the platform from the pool, allowed the mice to swim for 60 seconds, and measured the residence time within each quadrant region of the pool. In addition, the probe test was performed once for each mouse.
혈액의 혈당값은 혈당값 측정 장치(Roche diagnostics), HbA1c는 효소법 측정 키트(세키스이 메디컬)를 사용하여 측정했다. 혈장 중의 트리글리세리드, 총 콜레스테롤, LDL 콜레스테롤, HDL 콜레스테롤은 효소법 측정 키트(와코쥰야쿠고교)를 사용하여 측정했다. 혈장 중의 산화 LDL은 ELISA 키트(Kamiya Biomedical Company)를 사용하여 측정했다. 뇌내 Aβ펩티드 축적량은 ELISA 키트(와코쥰야쿠고교사)를 사용하여 측정했다. 취급 설명서의 프로토콜에 따라, 적출한 마우스 대뇌 샘플로부터 Aβ 획분을 조제하고, Aβ1-42 및 40 잔기로 이루어지는 Aβ 펩티드(Aβ1-40)를 각각 정량했다. 결과는 평균값 및 평균값의 표준 오차(SEM)로 나타냈다. 또한 Tukey-Kramer의 다중 비교에 따라 1원 배치 분산 분석을 행했다. 상이한 부호는 P<0.05에서 유의차가 있는 것을 나타낸다.Blood glucose values of blood were measured using a blood glucose value measuring device (Roche diagnostics) and HbA1c using an enzyme method measurement kit (Sekisui Medical). Triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol in plasma were measured using an enzyme method measurement kit (Wakkoyaku Kogyo). Oxidative LDL in plasma was measured using an ELISA kit (Kamiya Biomedical Company). Aβ peptide accumulation in the brain was measured using an ELISA kit (Wako Pure Chemical Industries, Ltd.). According to the protocol of the instruction manual, Aβ fractions were prepared from the extracted mouse cerebral samples, and Aβ peptides (Aβ1-40) each consisting of Aβ1-42 and 40 residues were quantified. The results are expressed as mean and standard error of the mean (SEM). One-way batch variance analysis was also performed according to Tukey-Kramer's multiple comparisons. Different symbols indicate a significant difference at P <0.05.
[결과][result]
18주간의 사육 후, 체중은 NC군과 PC군에서 유의한 차가 확인되었지만, 판토에아균 LPS 투여군과의 차는 확인되지 않았다. 공복일 때 혈당값은 NC군과 비교하여 PC군에서 명확한 증가, 및 PC군과 비교하여 판토에아균 LPS 투여군에서 유의하게 저하되었다. 마찬가지로, HbA1c는 NC군과 비교하여 PC군에서 명확한 증가, 및 PC군과 비교하여 판토에아균 LPS 1mg/kg 체중/day군에서 유의하게 저하되었다. 또한 간장 중량 및 정소 상체 주위 백색 지방 중량은 NC군과 비교하여 PC군에서 명확한 증가, 및 PC군과 비교하여 판토에아균 LPS 투여군에서의 유의한 저하가 확인되었다(표 1). 이것으로부터, 고지방 사료를 섭취한 마우스에서는, 2형 당뇨병 유사의 증상(혈당값이나 HbA1c값의 상승 등)을 발증하고 있고, 판토에아균 LPS의 투여에 의해, 당대사기능이 개선되는 것을 알 수 있다.After 18 weeks of breeding, body weight was significantly different between NC and PC groups, but not with Pantoea LPS-administered group. Fasting blood glucose levels were significantly increased in the PC group compared to the NC group, and significantly lower in the Pantoea LPS-administered group compared to the PC group. Similarly, HbA1c was significantly decreased in the PC group compared to the NC group, and significantly lower in the
혈중 지방질을 해석한 결과, 판토에아균 LPS 투여군에 있어서, 총 콜레스테롤 및 LDL 콜레스테롤의 명확한 저하가 확인되었다. HDL 콜레스테롤은, PC군과 비교하여, 판토에아균 LPS1mg/kg 체중/day군에서는 명확한 상승이 확인되었다. 또한 혈장의 산화 LDL은 판토에아균 LPS 0.3mg/kg 체중/day보다도 판토에아균 LPS1.0mg/kg 체중/day쪽이 PC군과 비교하여 낮은 값이 되었다(표 1). 이것으로부터, 고지방 사료를 섭취한 SAMP8 마우스에 있어서, 판토에아균 LPS의 경구 투여는 당 대사 및 지방질 대사를 개선하는 것을 알 수 있다. 지금까지, 나카다 등은 당뇨병 모델 마우스(KK-Ay)에 대한 판토에아균 LPS 배합(0.02%w/w) 차음료의 경구 투여 시험에 있어서, 물을 준 컨트롤군과 비교하여, 공복일 때 혈당값이 유의하게 저하된 것, 또한, 동 판토에아균 LPS 배합 차음료의 임상 시험(이중 맹검 무작위화 비교 시험)에 있어서, 당해 음료의 섭취에 의한 LDL 콜레스테롤의 저하 및 HDL 콜레스테롤의 증가를 보고했다(비특허문헌 10).As a result of analyzing blood lipids, a clear decrease in total cholesterol and LDL cholesterol was confirmed in the pantoea bacteria LPS-administered group. HDL cholesterol was clearly elevated in the pantoea bacteria LPS1 mg / kg body weight / day group compared with the PC group. In addition, the oxidized LDL of plasma was lower than the Pantoea LPS 1.0mg / kg body weight / day compared to the PC group than the Pantoea LPS 0.3mg / kg body weight / day (Table 1). From this, it can be seen that in SAMP8 mice fed high fat diet, oral administration of pantobacterial LPS improves glucose metabolism and lipid metabolism. So far, Nakada et al. Have been orally administering pantoea LPS combination (0.02% w / w) tea beverages to diabetic model mice (KK-Ay), compared to the control group that was given water, and fasting blood sugar when compared to the control group. Significantly lowered values, and also in clinical trials (double-blind randomized comparative trials) of the pantoea bacteria LPS blended tea beverages, reported a decrease in LDL cholesterol and an increase in HDL cholesterol by ingestion of the beverage. (Non-Patent Document 10).
수중 미로 시험의 트레이닝 시험을 행한 결과, 5일간의 트레이닝에 의해, 어느 군에서도 플랫폼 도달에 요하는 시간의 단축이 확인되었지만, 군 사이에 차는 확인되지 않았다(도 1). 트레이닝 시험의 다음날에 프로브 테스트를 행했다. 마우스의 수영 궤적은 각 군에 있어서 대표적인 데이터를 도 2에 나타냈다. 플랫폼이 설치되어 있던 4분원 영역의 체류 시간에 있어서, NC군과 비교하여, PC군에서 명확한 감소가 확인되었다. 또한 판토에아균 LPS 0.3mg/kg 체중/day보다도 판토에아균 LPS 1.0mg/kg 체중/day쪽이 PC군과 비교하여 긴 시간이 되었다(도 3). 수중 미로 시험에 근거한 학습 기능 평가의 결과로부터, 판토에아균 LPS의 경구 투여에 의해, 알츠하이머병 발증(노화 촉진) 모델 마우스의 학습기능에 관한 뇌기능이 개선되는 것을 알 수 있다.As a result of the training test of the underwater maze test, a shortening of the time required to reach the platform was confirmed in any group by the training for 5 days, but no difference was found between the groups (FIG. 1). The probe test was done the day after the training test. The swimming trajectory of the mouse is shown in Fig. 2 representative data for each group. In the residence time of the quadrant area in which the platform was installed, a clear decrease was confirmed in the PC group compared with the NC group. In addition, Pantoea LPS 1.0mg / kg body weight / day than Pantoea LPS 0.3mg / kg body weight / day was longer compared to the PC group (Fig. 3). From the result of learning function evaluation based on the underwater maze test, it turns out that the brain function regarding the learning function of Alzheimer's disease onset (aging promotion) model mouse improves by oral administration of Pantoea bacillus LPS.
뇌내의 Aβ 축적량을 ELISA에 의해 측정한 결과, Aβ1-40은 NC군과 비교하여 PC군에서 명확한 증가, 및 PC군과 비교하여 판토에아균 LPS 투여군에서 유의하게 저하되는 것이 확인되었다. 또한 Aβ1-42에 대해서는, NC군 및 PC군 사이에서는 유의한 차가 확인되지 않았지만, PC군과 비교하여 판토에아균 LPS 투여군에서 유의한 저하가 확인되었다(도 4). 이것으로부터, 판토에아균 LPS는 Aβ의 뇌내 축적을 억제함으로써 알츠하이머병의 발증(학습기능 기능 저하 등)을 억제하는 것을 알 수 있다.As a result of measuring Aβ accumulation in the brain by ELISA, it was confirmed that Aβ1-40 was significantly increased in the PC group compared to the NC group, and significantly lowered in the pantoea LPS-administered group compared to the PC group. Moreover, about Aβ1-42, although the significant difference was not confirmed between NC group and PC group, the significant fall was confirmed by the pantoea LPS administration group compared with PC group (FIG. 4). From this, it can be seen that Pantoea bacterium LPS suppresses the onset of Alzheimer's disease (decreases in learning function, etc.) by inhibiting accumulation of Aβ in the brain.
본 명세서에서 인용한 모든 간행물, 특허 및 특허출원은 그대로 참고로서, 여기에 포함되는 것으로 한다.All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.
또한, 명세서, 특허청구범위 및 도면을 포함한 2017년 5월 28일에 출원한 일본 특허출원 2017-105133의 개시는 그대로 참고로서, 여기에 포함되는 것으로 한다.In addition, the indication of the Japan patent application 2017-105133 for which it applied on May 28, 2017 including specification, a claim, and drawing is taken in as a reference as it is here.
Claims (5)
개선되는 뇌기능이 가령 또는 가령에 따른 뇌질환에 기인하여 저하된 인지 기능인 것을 특징으로 하는 식품 또는 의약품.The method of claim 1,
Food or pharmaceuticals, characterized in that the brain function to be improved is a cognitive function that is degraded due to, or according to, for example, a brain disease.
판토에아균 LPS를 유효량 함유하는 것을 특징으로 하는 뇌기능 개선제, 식품 또는 의약품.The method of claim 1,
A brain function improving agent, food or medicine comprising an effective amount of Pantoea LPS.
알츠하이머병을 예방하기 위한 것을 특징으로 하는 뇌기능 개선제, 식품 또는 의약품.The method of claim 1,
Brain function improving agent, food or medicine, characterized in that for preventing Alzheimer's disease.
판토에아균 LPS를 1일 투여 단위당 0.1∼1mg/kg 체중의 비율로 함유하는 것을 특징으로 하는 뇌기능 개선제, 식품 또는 의약품.The method of claim 1,
A brain function improving agent, food or medicine comprising Pantoea LPS at a ratio of 0.1 to 1 mg / kg body weight per day dosage unit.
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